The overall goal of this application is to understand the genetic basis of type 1 diabetes (T1D) and other autoimmune diseases. This knowledge can then be applied to their treatment, cure, and eventual prevention. In the case of T1D, the availability of several animal models, especially the NOD mouse, has complemented the efforts to localize human genes and has shown that some of the same genes, e.g. those encoding MHC class II molecules and the costimulatory molecule CTLA-4, are associated with TID in both species in a primary, causative way. There is also growing evidence that autoimmune diseases including T1D, autoimmune thyroid disease and multiple sclerosis (MS) are likely to be influenced by some of the same genes. For example, variation in the CTLA-4 molecule affects the course of both Graves' disease and T1D in humans and T1D and EAE in the mouse. The first aim is to determine if additional shared genes control the development of T1D in humans and mice. Idd10 and Idd18.2 contribute to the genetic control of T1D in NOD mice and may overlap with MS. The primary candidates in Idd10 are the polymorphic genes encoding B7H4 and CD101 and for Idd18.2, CD2 and IgSFS. Using novel congenic strains of mice and comparative sequence and expression studies, the candidacy of these genes will be tested. The influence of candidate genes defined by the Idd10 and Idd18.2 regions will be assessed in T1D using a staged genotyping strategy in a family collection (748 families) and a new case-control collection (> 4,000 T1D cases and 4,000 controls). The second aim focuses on the consequences of genetic variation in the human CTLA-4 gene. Peripheral blood cells from genotyped individuals, normal and patients with T1D, will be used to study the regulation of the soluble isoform of CTLA-4. In the third aim, the function of CD101, a costimulatory molecule whose expression is influenced by the CTLA4 genotype, will be studied in human peripheral blood cells and in a knockout mouse model.